Over 250,000 people in the United States, and several million worldwide, are permanently disabled due to a past spinal cord injury (chronic SCI), and about 12,000 people are newly injured (acute SCI) in the United States each year. Additionally, paralysis due to SCI is predominantly a condition of the young: 60% of spinal cord injuries occur before age 30, and the most frequent incidence is at age 19. Most injuries are caused by motor vehicle, sports or work-related accidents, or by violence. Estimated costs of care for SCI patients in the United States alone exceed $9 billion per year and over $1.5 million per patient lifetime.
Following trauma to the adult central nervous system (CNS) of mammals, injured neurons do not regenerate their transected axons. Currently, the mainstay of treatment in spinal cord injury is still rehabilitation. There is little one can do to address the primary injury. After spinal injury, three major classes of damage have been identified:    1. Neuronal cell death. The death of nerve cells due to injury presents a difficult problem because nerve cells lose the ability to undergo cell division as they mature into the highly specialized cells that make up our nervous systems. Some cells die during the traumatic insult, others die in the hours, days or even weeks following injury. Regardless of when the cell death occurs, functional connections cannot be established if the nerve cells no longer exist. Death of glia, also interferes with nerve function. The first therapeutic goal is to preserve as many cells as possible, also known as neuroprotection. Even with neuroprotective drugs or therapies, some nerve cell death is still likely in SCI. Therefore, replacement of nerve cells may be required.    2. Disruption of nerve pathways. The long axons in the ascending and descending tracts of the spinal cord undergo Wallerian degeneration after injury. Axonal regeneration must occur to re-establish neuronal circuits.    3. Demyelination. Myelin sheaths insulate the long, thin axons to facilitate nerve impulse transmission. In some types of SCI, as well as stroke and epilepsy, the nerve cells and axons may not be lost or interrupted; neuronal dysfunction may be due to loss of the myelin sheath. This type of damage may be the most amendable to treatment because rewiring of complex circuits may not be necessary and remyelination of axons is known to be possible.Possible Therapies1. Replacement of Nerve Cells
Mature nerve cells cannot divide to heal a wound. Replacement of lost nerve cells would require transplantation into the site of injury with the hope that grafted nerve cells would mature and integrate into the host nervous system. Use of human fetal tissue has shown promise in some studies, however, it presents ethical and technological considerations regarding donor tissues and important questions about immune rejection of transplanted cells. Very recently, scientists have discovered the presence of adult neural stem cells that can be stimulated to divide and develop into neurons and glia. This exciting finding has opened up new possibilities for cell therapy.
2. Regeneration of Damaged Axons
Neurons in both the central (CNS) and peripheral (PNS) nervous systems are intimately associated with glia. After injury, CNS glia largely inhibit regeneration, whilst in the PNS, the Schwann cells facilitate regeneration. The cells are seeded in specially designed “guidance channels” that have been shown to promote the regeneration of nerve fibres in severed rat spinal cords. Schwann cells and neurons produce growth factors. By introducing these factors into injury sites, alone or in combination with grafts, these have shown that they can stimulate additional spinal cord regeneration. Schwann cells can be genetically engineered to produce growth factors, and these also improve regeneration. Some improvement in hind limb motor function have been observed after grafting, however, the results are not reliable enough yet to justify clinical trials of these procedures. Two exciting new studies show that olfactory ensheathing glia can “usher” long nerve fiber growth into surviving spinal cord regions beyond the site of SCI, after these fibers exit a Schwann cell bridge or grow past the site of injury. These promising studies give hope that successful restoration of function after SCI, stroke or epilepsy may occur one day.
3. Remyelination of Axons
Schwann cells are the cells in peripheral nerves that form myelin sheaths. They are not usually found in the brain or spinal cord where oligodendrocytes are responsible for myelin production. Researchers have shown that Schwann cells grafted into the brain can myelinate central axons. When the loss of myelin is an important part of an injury, implanting Schwann cells could stimulate remyelination and perhaps restore function. A multi-center clinical trial has been initiated at other research centers to study a drug (4-AP) that appears to temporally restore signal transmission through demyelinated nerve fibers.
CNS Myelin and its Major Inhibitory Effects During Axonal Regeneration
An important barrier to regeneration is the axon growth inhibitory activity that is in CNS myelin and that is also associated with the plasma membrane of oligodendrocytes, the cells that synthesize myelin in the CNS. The growth inhibitory properties of CNS myelin have been demonstrated in a number of different laboratories by a wide variety of techniques, including plating neurons on myelin substrates or cryostat sections of white matter, and observations of axon contact with mature oligodendrocytes. Therefore, it is well documented that adult neurons cannot extend neurites over CNS myelin in vitro. It has also been well documented that removing myelin in vivo improves the success of regenerative growth over the native terrain of the CNS. Regeneration occurs after irradiation of newborn rats, a procedure that kills oligodendrocytes and prevents the appearance of myelin proteins. After such a procedure in rats and combined with a corticospinal trait lesion, some corticospinal axons regrow long distances beyond the lesions. Also, in a chick model of spinal cord repair, the onset of myelination correlates with a loss of its regenerative ability of cut axons. The removal of myelin with anti-galactocerebroside and complement in the embryonic chick spinal cord extends the permissive period for axonal regeneration. Known inhibitory molecules in myelin include myelin associated glycoprotein (MAG), tenascin-R (TN-R), arretin, and chondroitin-sulphate proteoglycans (CSPGs). Recently, three groups reported the identification in rats and humans of a gene, Nogo, which encodes an inhibitory myelin protein (GrandPre et al, 2000; Prinjha et al, 2000; Chen et al, 2000). Immunization against myelin has been found to allow extensive axon regeneration after injury,—this demonstrates the enormous potential value of overcoming myelin inhibition. These experiments demonstrate a good correlation between inhibitory factors in myelin and the failure of axons to regenerate in the CNS.
Multiple Sclerosis
MS is a degenerative central nervous system disorder involving decreased nerve function associated with the formation of scars on the insulating sheath known as myelin around nerve cells.
The cause of MS is not known. However, many researchers believe it may be an autoimmune disease, perhaps triggered by a viral infection. There is no definitive clinical test for the diagnosis of MS. However, an MRI (Magnetic Resonance Imaging) can show areas in the brain where myelin has been damaged.
MS affects approximately 250,000-300,000 people in the US. It predominantly afflicts women, Caucasians, and people from temperate climates. Generally, the onset of MS is diagnosed in people ages 20-40.
It is now well accepted that MS lesions contain substantial numbers of premyelinating oligodendrocytes, indicating that:                The potential for repair is not limited by the loss of these cells;        Interactions between oligodendrocytes and their surrounding environment may determine the outcome of the repair process.        